Polyiodinated compounds, their preparation and their use as contrast media for radiology

ABSTRACT

The present invention relates to polyiodinated compounds with a single molecular weight having a molecular concentration of iodine of greater than approximately 20% by weight, and in particular greater than approximately 30% by weight, containing at least 9 iodine atoms and having a molecular weight above 2000 and below approximately 50,000, and in particular above 2000 and below approximately 20,000, said compounds possessing either a zero overall electrical charge or at least two anionic charges, and persisting in the vascular compartment at a value equal to at least approximately 30% by weight of the injected dose in a subject five minutes after intravascular administration in the said subject.

The present invention relates to compounds which can be used as contrastmedia for X-ray radiology.

The present invention relates more especially to compounds which can beused as contrast media displaying a long residence in the vascularcompartment.

There is still a need for this type of product at the present time.

In effect, the traditional ionic or nonionic media customarily used,such as triiodinated derivatives of isophthalic acid, are very rapidlyextravasated. The time available for obtaining an image of the vascularcompartment of sufficient quality is thus very short.

To remedy this drawback, it has been proposed to repeat the injectionsof traditional contrast media. This approach entails, however, anincrease in doses and a higher risk of adverse side effects. It alsoresults in a greater cost of examinations of the vascular compartment.

Contrast media displaying a long residence in the vascular compartmentfor X-ray radiology have, moreover, been proposed; they are all based onthe principle of attachment of a number of iodinated molecules to a highmolecular weight polymer.

In this way, the contrast medium is excreted slowly by glomerularfiltration and remains confined in the vascular compartment, at leastfor a certain time.

There may be mentioned, in this connection, EP-354 836 and EP-344,202describing compounds possessing a dextran type backbone onto whichiodinated phenyl groups are grafted, EP 436,316 describing compoundswith polyacrylamide backbone onto which iodinated phenyl groups aregrafted or alternatively U.S. Pat. No. 5,019,370 describing compoundshaving a polyacrylate or polyamide backbone.

The major drawback of the products of the prior art lies, however, inthe polydispersity of the molecular weight of the polymers used, such asdextran or polylyine, or resulting from the copolymerization of theacrylamide type monomers used.

This polydispersity has several drawbacks: in the first place, the lowmolecular weight components of the iodinated polymer are excretedrapidly and no longer contribute to the concentration which is usefulfor obtaining the vascular image.

In addition, extravasation of the low molecular weight polymers into theinterstitial compartment decreases the contrast at the interface betweenthe vascular and interstitial compartments, and results in an image ofinsufficient quality.

Lastly, the high molecular weight components of the iodinated polymerare eliminated only very slowly via the kidneys or by uptake by thereticuloendothelial system, and may generate undesirable anaphylactoidreactions.

Hence the compounds proposed hitherto do not permit the confinement of acontrast medium in the vascular compartment, or its biocompatibility, tobe controlled in a precise manner.

Polyiodinated compounds comprising up to 3 phenyl rings are, moreover,known from FR 2,272,640.

These compounds are not, however, described as being capable ofdisplaying a long residence in the vascular compartment.

The objective of the present invention is to provide compounds which canbe used as contrast media for X-ray radiology which do not possess thedrawbacks of the compounds of the prior art while displaying a goodresidence time in the vascular compartment.

The subject of the invention is polyiodinated compounds with a singlemolecular weight having a molecular concentration of iodine of greaterthan approximately 20% by weight, and in particular greater thanapproximately 30% by weight, containing at least 9 iodine atoms andhaving a molecular weight above 2000 and below approximately 50,000, andin particular above 2000 and below approximately 20,000, characterizedin that they have either a zero overall electrical charge or at leasttwo anionic charges, and in that they persist in the vascularcompartment at a value equal to at least approximately 30% by weight ofthe injected dose in a subject five minutes after intravascularadministration in the said subject.

Single molecular weight is understood, in the context of the presentinvention, to mean a molecular weight which is not defined as an averageof the different molecular weights present for the same compound, asopposed to the dispersity of the molecular weights of the polymers ofthe prior art mentioned hereinbefore.

In other words, a compound according to the invention, possessing asingle molecular weight, is understood to mean a product possessing anindex of polydispersity equal to 1.

The subject of the invention is, in particular, polyiodinated compoundswhich are characterized in that they contain at least one group offormula ##STR1## with w=Σ₀ ^(n) 2^(n) and w'=2^(n), n representing aninteger from 0 to 4,

the groups Q, which may be identical to or different from one another,represent a single bond or a group selected from: ##STR2## in which: R₁is selected from an alkylene group having a linear or branched C₁ -C₁₀chain, a hydroxy- or polyhydroxyalkylene group having a linear orbranched C₁ -C₁₀ chain, a (C₁ -C₅ alkoxy)alkylene group having a linearor branched C₁ -C₁₀ chain, a hydroxy- or polyhydroxy(C₁ -C₅alkoxy)alkylene group having a linear or branched chain, and a singlebond, and

the groups R₂, which may be identical or different, are selected from H,an alkyl group having a linear or branched C₁ -C₁₀ chain, a hydroxy- orpolyhydroxyalkyl group having a linear or branched C₁ -C₁₀ chain, a (C₁-C₅ alkoxy)alkyl group having a linear or branched C₁ -C₁₀ chain and ahydroxy- or polyhydroxy(C₁ -C₅ alkoxy)alkyl group having a linear orbranched chain;

the groups B₁, which may be identical to or different from one another,represent the residue of an aromatic group containing at least threeiodine atoms and are preferably selected from the groups of formulae:##STR3## in which R₃ is selected from:

a group --COO⁻ M⁺ with M⁺ representing H⁺ or a physiologicallyacceptable cation of an organic or inorganic base,

a group ##STR4## and a group ##STR5## in which R₅ and R₆, which may beidentical to or different from one another, represent H or a linear orbranched C₁ -C₁₀ alkyl, linear or branched C₁ -C₁₀ hydroxy- orpolyhydroxyalkyl, linear or branched C₁ -C₁₀ (C₁ -C₅ alkoxy)alkyl orlinear or branched C₁ -C₁₀ hydroxy- or polyhydroxy(C₁ -C₅ alkoxy)alkylgroup, a C₁ -C₆ alkyl group substituted with one or more (preferablyfrom 1 to 9) hydroxy- or polyhydroxyalkoxy group(s) or a C₁ -C₆ hydroxy-or polyhydroxyalkyl group substituted with one or more (preferably from1 to 9) C₁ -C₁₀ hydroxy- or polyhydroxyalkoxy group(s)

or R₅ and R₆ together form a C₄ -C₈ alkylene, C₄ -C₈ hydroxyalkylene orC₄ -C₈ polyhydroxyalkylene group having a linear or branched chain whichis optionally interrupted by one or more atoms chosen from S, O, P andN, so that R₅ and R₆, with the nitrogen atom to which they are linked,form a 5- to 12-membered nitrogenous heterocycle optionally substitutedwith one or more hydroxyl groups or C₁ -C₄ hydroxy- or polyhydroxyalkylgroups having a linear or branched chain and optionally containing oneor more additional hetero atoms selected from S, O, P and N,

R₄ represents a group selected from R₃ and a group of formula Q--B₄, Qbeing as defined above and B₄ representing a group: ##STR6## in which R₇and R₈, which may be identical to or different from one another,represent R₃,

the groups B₃, which may be identical to or different from one another,are selected from: ##STR7## in which R₅ has the meanings given above.

In a further aspect, the invention relates more especially topolyiodinated compounds of generic formula I:

    A.paren open-st.X).sub.m                                   (I)

in which:

A represents the residue of a polyfunctional molecule containing eithera central tri- or tetrasubstituted carbon atom and/or at least onearomatic or non-aromatic carbocycle optionally containing one or moreiodine atoms, or at least one aromatic or non-aromatic heterocyclecontaining from 1 to 4 hetero atoms chosen from O, S, N and P, to whichmolecule are bound m groups X via m bonds or via m groups selected from--C--, ##STR8## --O--, >NCOR₅ ; the groups X, which may be identical toor different from one another, represent the groups:

    --Q--B.sub.1                                               (A),

    --Q--A.sub.1 --(Q--B.sub.1).sub.m                          (B),

m' representing from 2 to 11; or

    --Q--B.sub.2 --Q--B.sub.1                                  (C)

or

the groups X, which may be identical or different, represent: ##STR9##with w, w', Q, B₁ and B₃ as defined above, m represents an integer from3 to 12 when X represents the groups (A), (B) or (C), and from 2 to 12when X represents the group (D),

A₁ is selected from the groups A, with the proviso that at least onegroup --CO--, ##STR10## or ##STR11## is replaced by a single bond, B₂ isselected from the groups: ##STR12## in which R₄ and R₅ have the meaningsgiven above; with the proviso that the said compounds contain a zerooverall electrical charge or at least two anionic charges whenA--(--X)_(m) =A--(--QB₁)₃, and that said compounds have a molecularweight above 2000 and below approximately 50,000.

Advantageously, in a further aspect, the invention relates to compoundsof generic formula I as described above, in which:

A represents a residue of a polyfunctional molecule containing a centralcarbon atom, selected from a residue of formula CR₉ (R₁₀ --Y--)₃ -- inwhich R₉ represents a hydrogen atom, a C₁ -C₆ alkyl or C₅ -C₁₀ arylgroup or a group (R₁₀ --Y), R₁₀ being chosen from a C₁ -C₆ alkylene, C₅-C₁₀ arylene, (C₁ -C₁₀ alkyl)(C₅ -C₁₀ arylene) and (C₅ -C₁₀ aryl)(C₁ -C₆alkylene) group, it being possible for the alkylene groups to beoptionally interrupted by one or more oxygen atoms, and the alkyl,alkylene, aryl or arylene groups being optionally substituted with oneor more OH groups,

Y being selected from an --O--, --CO-- group or a group ##STR13##>NCOR₅, R₅ being as defined above, or A represents an optionallypolycyclic C₅ to C₁₂ cycloalkane residue optionally containing from 1 to6 iodine atoms and from 2 to 12 identical or different substituents offormula --R₁₁ --(Y)_(q), q representing an integer from 1 to 3, R₁₁being a single bond or a linear or branched C₁ -C₆ alkylene groupoptionally substituted with one or more OH groups and/or interrupted byone or more oxygen atoms, and Y being as defined above,

or A represents a monocyclic or bicyclic C₅ -C₁₂ aromatic hydrocarbonresidue optionally containing from 3 to 6 iodine atoms and optionallycontaining one or more substituents selected from OH, NH₂, C₁ -C₆ alkyl,C₁ -C₆ hydroxy- or polyhydroxyalkyl, COOH, COOR₁₂, --CO--NHR₁₂ or --NR₆COR₅, R₁₂ representing a C₁ -C₄ alkyl group and containing from 2 to 12substituents of formula --R₁₁ --(--Y--)_(q), q and R₁₁ being as definedabove and Y representing a group selected from --O--, --CO--, ##STR14##or A represents an optionally aromatic monocyclic or bicyclicheterocyclic residue containing from 5 to 10 ring-members including 1 to4 hetero atoms selected from O, S, N and P, optionally substituted with3 to 6 identical or different substituents selected from ═O, andcontaining from 3 to 12 substituents of formula --R₁₁ --(--Y--)_(q), Yand q being as defined above;

or A represents an optionally cyclic residue containing from 2 to 18aromatic or heterocyclic ring-systems as defined above, linked to oneanother through groups --R₁₁ --, --OR₁₁ --, R₁₁ being as defined above,this residue containing from 3 to 12 substituents of formula --R₁₁--(--Y--)_(q), R₁₁, Y and q being as defined above,

the groups X, which may be identical or different, represent the groups:

    --Q--B.sub.1,                                              (A)

    --Q--A.sub.1 --(Q--B.sub.1).sub.m',                        (B)

m' representing from 2 to 11; or

    --Q--B.sub.2 --Q--B.sub.1,                                 (C)

or

X represents a group: ##STR15## and w=Σ₀ ^(n) 2^(n) and w'=2^(n), nrepresenting an integer from 0 to 4,

m represents an integer from 3 to 12 when X represents the groups (A),(B) or (C), and from 2 to 12 when X represents the group (D),

the groups Q, which may be identical to or different from one another,represent a single bond or a group selected from: ##STR16## in which: R₁is selected from a single bond, an alkylene group having a linear orbranched C₁ -C₁₀ chain, a hydroxy- or polyhydroxyalkylene group having alinear or branched C₁ -C₁₀ chain, a (C₁ -C₅ alkoxy)alkylene group havinga linear or branched C₁ -C₁₀ chain and a hydroxy- or polyhydroxy(C₁ -C₅alkoxy)alkylene group having a linear or branched chain, the alkylenechain being optionally interrupted by one or more oxygen atoms, inparticular 1 to 4,

R₂ is selected from H, an alkyl group having a linear or branched C₁-C₁₀ chain, a hydroxy- or polyhydroxyalkyl group having a linear orbranched C₁ -C₁₀ chain, a (C₁ -C₅ alkoxy)alkyl group having a linear orbranched C₁ -C₁₀ chain and a hydroxy- or polyhydroxy(C₁ -C₅ alkoxy)alkylgroup having a linear or branched chain;

A₁ is selected from the groups A, with the proviso that at least onegroup --CO--, ##STR17## or >NCOR₅ is replaced by a single bond; thegroups B₁, which may be identical to or different from one another,represent the residue of an aromatic group containing at least threeiodine atoms and are preferably selected from the groups of formula:##STR18## in which R₃ is selected from:

a group --COO⁻ M⁺ with M⁺ representing H⁺ or a physiologicallyacceptable cation of an organic or inorganic base, in particular Na⁺,Ca⁺, Mg⁺, glucamine, methylglucamine, lysine or arginine,

a group ##STR19## and a group ##STR20## in which R₅ and R₆, which may beidentical to or different from one another, represent H or a linear orbranched C₁ -C₁₀ alkyl, linear or branched C₁ -C₁₀ hydroxy- orpolyhydroxyalkyl, linear or branched C₁ -C₁₀ (C₁ -C₅ alkoxy)alkyl orlinear or branched C₁ -C₁₀ hydroxy- or polyhydroxy(C₁ -C₅ alkoxy)alkylgroup,

or R₅ and R₆ together form a C₄ -C₈ alkylene, C₄ -C₈ hydroxyalkylene orC₄ -C₈ polyhydroxyalkylene group having a linear or branched chain whichis optionally interrupted by one or more atoms selected from S, O, P andN, so that R₅ and R₆, with the nitogen atom to which they are linked,form a 5- to 12-membered nitrogenous heterocycle optionally substitutedwith one or more hydroxyl groups or C₁ -C₄ hydroxy- or polyhydroxyalkylgroups having a linear or branched chain and optionally containing oneor more additional hetero atoms selected from S, O, P and N,

R₄ represents a group selected from R₃ and the groups of formula Q--B₄,Q being as defined above and B₄ representing a group ##STR21## in whichR₇ and R₈, which may be identical to or different from one another,represent R₃ as defined above, B₂ is selected from the groups: ##STR22##in which R₄ and R₅ have the meanings given above; the groups B₃, whichmay be identical to or different from one another, are selected from:##STR23## in which R₅ has the meaning given above, with the proviso thatthe said compounds contain a zero overall electrical charge or at leasttwo anionic charges when A--(--X)_(m) =A--(--QB₁)₃, and that the saidcompounds possess a molecular weight above 2000 and below approximately50,000.

The products of the invention in which the group X is a group (D)correspond, for example, to the formula

below:

with n=2, w=7 and w'=4, the following compound is obtained: ##STR24##

It is self-evident that the invention encompasses not only compounds offormula (I) in the form of a racemic mixture, but also stereoisomerssuch as enantiomers, diastereoisomers, atropoisomers and syn-anti,endoexo and E-Z isomers, associated with the presence of asymmetriccarbon atoms and/or with obstructions to rotation due to the sterichindrance brought about by the iodine atoms and/or the substituents R ofthe compounds of the invention.

Among the different types of group A, there may be mentioned:

A) a residue of formula C(R₁₀ --y--)₄, R₁₀ representing a group(CH₂)_(n).sbsb.1 with n₁ =1 to 5, optionally interrupted by 1 to 4oxygen atoms, in particular a methylene group or a --CH₂ --O--CH₂ -- or--CH₂ --O--(CH₂)₂, or a phenylene or phenylmethylene group, and Y beingas defined above,

and more especially the following groups: ##STR25## described in J.Chem. Soc. (1922), 1638; ##STR26## described in Angew. Chem. Int. Ed.Eng., 25, 1097, 1986; ##STR27## described in U.S. Pat. No. 3,994,972J.C.S., 1938, 1588-1595 ##STR28## described in F. A. Neugebauer, Chem.Ber., 109, 2389, 1976 ##STR29## described in Angew. Chem. Int. Ed. Engl.25, 1097, 1986 and JACS, 101, 2728, 1979.

B) a cycloalkane residue selected from cyclohexane and adamantane,substituted with 3 or 4 substituents R₁₁ --(Y--)_(q) as defined above,and in particular the following groups: ##STR30## described in Newkome,J. Org. Chem., 57, 358, 1992;

C) a phenyl group optionally substituted with 3 to 4 iodine atoms or abiphenyl group optionally substituted with 4 to 6 iodine atoms andoptionally containing from 3 to 6 substituents of formula --R₁₁--(Y--)_(q), R₁₁ and Y being as defined above, in particular thefollowing groups: ##STR31## J. Org. Chem. 50 (1985) 2001 J. Am. Chem.Soc. 108 (1986) 849

J. Chem. Soc. Chem. Comm. 1986, 752 ##STR32##

D) a heterocyclic residue consisting of a 2,4,6-trioxo-1,3,5-triazinegroup substituted on the nitrogen atoms with 3 substituents of formula

--R₁₁ --(Y₁ --)_(q) as defined above, and in particular the groups:##STR33##

E) a macrocycle containing 6 to 8 phenyl residues each substituted withone or more substituents selected from OH, NH₂, C₁ -C₆ alkyl, C₁ -C₆hydroxy- or polyhydroxyalkyl, COOH, COOR₁₂, --CO--NHR₁₂ -- and --NR₆COR₅, R₁₂ representing a C₁ -C₄ alkyl group, and one or more groups ofthe formula R₁₁ --(Y--) q as defined above with q=1, the phenyl residuesbeing linked to one another through a methylene group, or a cyclodextrincontaining 6 to 8 glucosyl residues linked to one another through aglycosidic linkage, one or more OH groups of the said glucosyl residuesbeing optionally substituted with a carboxymethyl residue, one or moreOH groups of the said glucosyl residues being replaced by an --O--group, or a macrocycle containing more than one nitrogen, such as1,4,7,10-tetraazacyclododecane or 1-oxo-4,7,10-triazacyclododecane, or aderivative of a polyaminocarboxylic acid, such as DOTA(1,4,7,10-tetraazacyclododecanetetraacetic acid) or DO3A(1,4,7,10-tetraazacyclododecanetriacetic acid), in particular theresidues:

calixarene derivatives having eight rings, of formula: ##STR34## theresidues derived from α-, β- and γ-cyclodextrins and carboxymethyl-α-,-β- and -γ-cyclodextrins (U.S. Pat. No. 4,247,535, Carbohydr. Res. 63,13 (1978)) by elimination of one or more H atoms on the glucosylresidues;

DOTA, DO3A.

The group B, is advantageously selected from: ##STR35##

The group B₃ is advantageously selected from: ##STR36##

The group Q is advantageously selected from: ##STR37## r being aninteger from 1 to 5.

R₃ is advantageously selected from: ##STR38##

R₄ is advantageously selected from the groups R₃ and a group of formula--Q--B₄, Q being as defined above and B₄ representing a group offormula: ##STR39## R₇ R₈ having the same meanings as R₃.

A first group of preferred compounds according to the invention isrepresented by the compounds of the generic formula II:

    A--(--Q--B.sub.1).sub.3                                    (II)

A and B₁ being as defined above and Q represents a group: ##STR40##

A second group of preferred compounds according to the invention isrepresented by the compounds of the generic formula III:

    A-- --Q--A.sub.1 --(Q--B.sub.1).sub.2 !.sub.3              (III)

in which:

A and A₁ are as defined above,

Q represents a group ##STR41## A₁ represents a group ##STR42## and B₁represents a group ##STR43## R₃ and R₄ being as defined above.

A third group of preferred compounds according to the invention isrepresented by the compounds of the general formula IV:

    A--(--Q--B.sub.2 --Q--B.sub.1).sub.3                       (IV)

in which A and B₁ are as defined above,

Q represents a group ##STR44## and B₂ represents a group ##STR45## R₄being as defined above.

A fourth group of preferred compounds according to the invention isrepresented by the compounds of general formula V: ##STR46## w=Σ₀ ^(n)2^(n) and w'=2^(n) (n representing an integer from 0 to 4)

in which formula A and B₁ are as defined above,

Q preferably represents a group ##STR47## and B₃ represents a group:##STR48##

These compounds have a branched structure, each group B₃ being linked tothree groups Q. The degree of branching (n) can range up to 4. Thus, thestructure of these compounds obeys a geometric progression of commonratio 2 as defined above.

Preferred compounds of the invention are also those in which the groupsX differ from one another. For example, a compound of the invention isthat which has the formula below: ##STR49## and two groups X=--Q--B.

The following compound is thereby obtained: ##STR50## With A= ##STR51##the following compound is obtained: ##STR52##

Preferred groups of compounds in which M⁺ has one of the definitionsstated above, have the following general formulae: ##STR53##

Among preferred compounds, the following compounds may be mentioned:##STR54##

In a further aspect, the invention relates also to a process forpreparing the polyiodinated compounds as defined above, characterized inthat they are obtained, either:

1.i) by activation of a compound of formula A'(OH)_(m), A' representingA as defined above and having m groups Y representing --CO, m being asdefined above, the OH groups of A' being optionally protected by aprotective group, with a chlorinating reagent to obtain a polyacidchloride of the formula:

    A'.paren open-st.Cl).sub.m'

followed by a

ii) coupling of the compound of formula:

    A'.paren open-st.Cl.sup.-).sub.m

with m compounds of formula X'H, X' representing a group X as definedabove in which Q, A₁, B₂, B₃ contains at least one group --NH--, --NR₅--, R₅ being as defined above, the OH groups of X' being optionallyprotected by a protective group, to obtain a compound of formula:

    A'.paren open-st.X').sub.m

iii) and deprotection of the protected hydroxyl groups of A' and X' soas to obtain a compound of formula A.paren open-st.X)_(m')

or

2.i) by direct activation of a compound of formula A'(OH)_(m), asdefined above,

ii) coupling of the above compound with m compounds of formula X'H, X'being as defined above, so as to obtain a compound of formula:

    A'.paren open-st.X').sub.m

as defined above; and

iii) deprotection of the protected OH groups of A' and X' to obtain acompound of formula:

    A.paren open-st.X).sub.m'

or

3.i) by reaction of a compound of formula A'(H)_(m') in which A'represents a group A as defined above containing m groups Y representing--NH or --NR₅ and m being as defined above, the OH groups of A' beingoptionally protected by a protective group, with

m acid chlorides of formula X'.paren open-st.Cl)_(m'), X' representing agroup X as defined above containing at least one --CO group, the OHgroups of which are optionally protected, so as to obtain a compoundA'--(--X')_(m) ' deprotection of the OH groups of A' and X' so as toobtain a compound of formula A.paren open-st.X)_(m) ;

ii) reaction of a compound of formula A'.paren open-st.H)_(m), in whichA' represents a group A as defined above containing a group Yrepresenting --O-- or >NCOR_(5'), the --OH groups of A' being optionallyprotected by a protective group, with

m compounds of formula X'--L, X' representing a group X as definedabove, the OH groups of which are protected, and L represents a leavinggroup,

so as to obtain a compound of formula A'.paren open-st.X')_(m) asdefined above, deprotection of the OH groups A' and X' so as to obtainthe compound of formula:

    A.paren open-st.X).sub.m.

The reaction of step 1.i) takes place with a chlorinating reagent suchas SOCl₂ PCl₅ or (CO)₂ Cl₂ in a solvent such as DMAC, DMF, ethyl acetateor dichloromethane.

The reaction of step 1.ii) preferably takes place in a solvent such asDMF, DMAC or dichloromethane.

The reaction of step 2.i) takes place in the presence of a couplingreagent, in particular 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or1,3-dicyclohexylcarbodiimide, in a solvent such as DMAC, DMF,dichloromethane or water, optionally in the presence of a catalyst suchas 1-hydroxy-1H-benzotriazole.

The reaction of step 3.i) is preferably carried out in a solvent such asDMF, DMAC, CH₂ Cl₂ or dioxane.

The acid chlorides of step 3.ii) of formula X"CO--Cl are obtained, forexample, from the corresponding compounds of formula X"COOH with areagent such as SOCl₂, PCl₅ or (CO)₂ Cl₂ in an organic solvent such asDMAC, DMF or CH₂ Cl₂.

The leaving group L of step 3.ii) is preferably chosen from O-tosyl andO-mesyl groups and a halogen atom (Cl, Br, I).

The starting materials of formula A'(H)_(m) or A"(COOH)_(m) are obtainedas described in the publications cited above with reference to thecorresponding group A, or obtained from products sold on the market (forexample α-, β- and γ-cyclodextrins marketed by Sigma, France) orprepared as described below.

The binding of the groups Q to the groups B₁, B₂ and B₃ is carried outin a manner known per se by acylation, amidation or alkylation reactionsof the groups B in solvents such as DMF, DMAC or CH₂ Cl₂, optionally inthe presence of a base, in particular for the alkylation reactions.

The triiodinated starting materials corresponding to the groups B₁, B₂and B₃ are obtained, in particular, according to the methods describedin FR-A-2,272,640, FR-A-2,632,304, FR-A-2,673,180 and FR-A-2,656,865, orin the work "Radio Contrast Agents" (Sovak H. Ed. Sovak, Berlin, NewYork, Springer 1984).

When X represents a group D as described above, the compounds of genericformula I may be obtained from a compound of generic formula VI:##STR55## in which Q', B'₁ and B'₃ represent, respectively, the groupsQ, B₁ and B₃, the OH groups of which are optionally protected, w and w'are as defined above and P is either a hydrogen atom, or a standardprotective group for the amino or carboxyl group, or a leaving group(for example Cl, Br, I, OTs, OMs), which is coupled, after deprotectionby removal of the group P, with the core of the molecule A by acylationor alkylation (reductive amination) reactions well known to a personskilled in the art, and the optionally protected OH functions are thendeprotected to obtain the desired compound of generic formula I.

For example, coupling of the compounds of generic formula II is carriedout with a compound of formula A'(OH)_(m), for example trimesic acid,after activation of the carboxyl groups, for example using acarbodiimide, followed by a possible acylation of the free aminefunctions of the compound of general formula VI.

The compound of general formula VI may be prepared from the intermediatecompounds of the following formulae VII and VIII:

    P--Q'-B'.sub.3 (L).sub.2                                   VII

    P--Q'--B'.sub.1                                            VIII

in which P represents H, or a protective group for primary or secondaryamine functions which is well known to a person skilled in the art, suchas a phthalimido group, or a protective group for the carboxyl function,and Q', B'₁ and B'₃ represent, respectively, the groups Q, B₁ and B₃ inwhich the hydroxyl functions present are optionally protected, and Lrepresents a leaving group (for example Cl, Br, I, OTs or OMs).

Thus, for n=0, the compound of formula VIII is deprotected by removal ofthe protective group P (for example by hydrazinolysis of the phthalimidogroups), and the compound thus deprotected (for example the amine)obtained is reacted with a compound of formula VII (for example a diacidchloride) in standard solvents (DMAC, DMF, U-methylpyrrolidone, etc) inthe presence of an organic or inorganic base to obtain a compound offormula ##STR56##

For n=1, after removal of the protective group P (for example byhydrazinolysis of the phthalimido groups), the compound obtained aboveis reacted with a compound of formula VII under the same conditions toobtain a compound of formula IX ##STR57##

For n=2, 3, 4, the compound obtained at the end of each step, theprotective group of which has been removed, is reacted in the samemanner with a compound of formula VII to obtain a compound of genericformula VI.

The subject of the invention is also the intermediate compounds offormula VI as defined above.

The subject of the invention is also contrast media which comprise atleast one compound of formula I.

These contrast media are used in man and animals for radiologicalpurposes.

The preferred pharmaceutical dosage form of the contrast media accordingto the invention consists of aqueous solutions or of suspensions of thecompounds, preferably in double-distilled water. It can also take theform of a powder.

The aqueous solutions of the compounds of formula I can also containcertain additives, such as:

sodium chloride at concentrations between 0.1 and 10 mM,

disodium EDTA at concentrations of between 0.1 and 2 mM,

sodium citrate at concentrations of between 0.1 and 10 mM,

tris(hydroxymethyl)aminomethane hydrochloride,

tris(hydroxymethyl)aminomethane amine,

heparin at concentrations of between 10 and 100 units per 100 ml ofsolution,

sodium calcium edetate.

For use in X-ray radiography, the contrast medium according to theinvention is administered at a useful dose varying from approximately 1to 1000 ml of aqueous solution, in order to obtain concentrationsvarying from approximately 0.01 g of iodine/kg body weight toapproximately 5 g of iodine/kg body weight, and preferably fromapproximately 0.1 g of iodine/kg body weight to 2 g of iodine/kg bodyweight.

These compositions may be administered via all the routes traditionallyused for iodinated contrast media. Thus, when they occur in solution,they may be administered enterally or parenterally (oral, rectal,intravenous, intra-arterial, intra-articular or subarachnoid route, aswell as via the bronchial, lymphatic and intra-uterine routes);preferably, the compounds are administered intravascularly.

When they take the form of a suspension in water or the form of a powderin a physiologically acceptable pharmaceutical formulation, thecompositions according to the invention are preferably administeredenterally, orally, rectally or bronchially.

The compositions of the invention can, in addition, take the form ofliposomes, the compounds of formula I being encapsulated inside theseliposomes.

In the case of an injection, the latter may be carried out by bolus orin perfusion.

An example of composition according to the present invention will begiven below.

    ______________________________________                                        Composition A                                                                 Compound of Example 1                                                                           35.77       g                                               Water for injections Q.S.                                                                       100         ml.                                             Composition B                                                                 Compound of Example 1                                                                           53.65       g                                               Water for injections Q.S.                                                                       100         ml.                                             ______________________________________                                    

The subject of the invention is also a method of X-ray diagnosis, inparticular of a subject's vascular compartment, characterized in that itcomprises the intravenous or intra-arterial administration of a contrastmedium as defined above, in a sufficient amount to render the saidsubject's vascular compartment opaque to X-rays, and the exposure of thesaid subject to a defined dose of X-rays, the injected dose varying fromapproximately 0.1 g of iodine/kg body weight to approximately 5 g ofiodine/kg body weight, and preferably from approximately 0.1 g ofiodine/kg body weight to approximately 2 g of iodine/kg body weight.

The preparation of intermediates compounds, as well as a few examples ofcompounds according to the invention, will be described below.Preparation of the compound AH₃ of formula: ##STR58## 1) Preparation ofN,N',N"-tris(2,3-epoxypropyl)-1,3,5-triazine-2,4,6(1H,3H,5H)-trione##STR59##

74 g (0.43 mol) of 70% meta-chloroperbenzoic acid suspended in 400 ml ofdichloromethane are added to a mixture of 10 g (0.04 mol) ofN,N',N"-triallyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione (commerciallyavailable from Aldrich--Strasbourg--France) and 100 ml ofdichloromethane. Stirring is maintained for 6 days at room temperature.

After cooling and returning to room temperature, the solution isfiltered; the peroxides contained in the filtrate are neutralized with35 ml of 10% sodium sulphite solution. The organic phase is separatedafter settling has taken place and washed with twice 100 ml of 5% sodiumbicarbonate solution. After settling has taken place, the organic phaseis separated, dried over magnesium sulphate and evaporated.

10 g of white powder are obtained, equivalent to an 84% yield.

2) Preparation ofN,N',N"-tris(2-hydroxyethyl-iminodibenzyl)-1,3,5-triazine-2,4,6(1H,3H,5H)-trione##STR60##

4.97 g (0.025 mol) of dibenzylamine are added to a solution of 2.5 g(0.008 mol) ofN,N',N"-tris(2,3-epoxypropyl)-1,3,5-triazine-2,4,6(1N,3H,5H)-trione in10 ml of dichloromethane. Stirring is maintained for two days at roomtemperature. The reaction medium is evaporated, and the product obtainedis purified by chromatography with ethyl acetate. After evaporation ofthe organic phase, 3.6 g of beige powder are obtained, equivalent to a50% yield.

3) Preparation ofN,N'N"-tris(2-amino-3-hydroxypropyl)-1,3,5-triazine-2,4,6(1H,3H,5H)-trione##STR61##

2 g of (0.002 mol) ofN,N',N"-tris(2-hydroxyethyliminodibenzyl)-1,3,5-triazine-2,4,6(1H,3H,5H)-trionedissolved in 200 ml of methanol are hydrogenated at 8 bars and at 50° C.in the presence of hydrated palladium or charcoal (palladium content50%) for 3 hours.

After filtration and evaporation, 500 mg of a white powder are obtained,equivalent to a 70% yield. ##STR62## Preparation of the compound A(OH)₃of formula: ##STR63##

1) Esterification of sarcosine

The esterification of sarcosine is carried out according to the methoddescribed in Agric. Biol. Chem., 50 (3) 615, 1986.

2) Chlorination of the trimesic acid

73 g (0.35 mol) of trimesic acid (commercially available from thecompany SIGMA, France) are suspended in 300 ml of thionyl chloride.After reflux for 24 h, removal of the thionyl chloride and vacuumdistillation, the acid trichloride is obtained in the form of a whitesolid.

(88.1 g, Yield: 95.5%, M.p.: 35° C.)

2.62 g (0.019 mol) of sarcosine ester in hydrochloride form, obtainedabove, 6.55 ml (0.047 mol) of triethylamine and then 1 g (0.0038 mol) oftrimesic acid trichloride are added slowly to dichloromethane. After 6 hof reflux, cooling and filtration, 1.55 g of product in the form of atriester are obtained, equivalent to an 89% yield.

Rf (CH₂ Cl₂ /MeOH 9:1): 0.47

¹ H NMR DMSO-d₆ 200 MHz

2.99 (s, 9H, NH--CH₃); 3.68 (s, 9H, CO₂ CH₃); 4.16 (s, 6H, CH₂); 7.43(s, 3H, CH).

3) Saponification of the triester

0.61 g (0.0013 mol) of the triester prepared in the preceding step isdissolved in 8 ml of methanol. 0.52 g (0.013 mol) of sodium hydroxidedissolved in 2 ml of water is added. After 12 h at room temperature,acidification, filtration and evaporation, 0.55 g of triacid isobtained.

¹ H NMR DMSO-d₆ 200 MHz

2.95 (s, 9H, CH--CH₃); 4.1 (s, 6H, CH₂); 7.4 (s, 3H, CH); 7.77 (s, 3H,COOH).

Preparation of the compound AH₄ of formula: ##STR64##

The preparation is carried out from the compound: ##STR65## preparedaccording to the method described in Angew. Chem. Int. Ed. Engl. 25,1986, 1097.

The conversion -phenyl-CO₂ H→phenyl-NH₂ is carried out according to themethod described in JACS, 101, p. 2728, 1979.

EXAMPLE 1

Preparation of the compound of formula: ##STR66##

4 g (0.019 mol) of trimesic acid, 37.11 g (0.059 mol) of3-(N-methylcarbamoyl)-5-aminoacetamido-2,4,6-triiodobenzoic acidprepared according to the method described in U.S. Pat. No. 4,014,986,10.49 g (0.0685 mol) of hydroxybenzotriazole, 10 ml of triethylamine and13.14 g (0.0685 mol) of 1-(3-dimethylaminopropyl)-3-ethylcarboduimidehydrochloride (EDCI) are dissolved in 1 of DMF. After stirring at roomtemperature for 12 h followed by evaporation of the solvent, the residueis triturated in CH₂ Cl₂. The solid obtained is purified by dissolutionin aqueous ammonia and then precipitated in an acid medium.

32.7 g of product in the form of white powder are obtained, equivalentto an 84% yield.

TLC SiO₂ (AcOEt/isopropanol/NH₃, 35:35:40)

Rf: 0.16

¹ H NMR DMSO-d₆ 200 MHz

2.7 (s, 9H, CH₃); 3.3 (m, 3H, CO₂ H); 4.2 (s, 6H, CH₂); 8.45 (dq, 3H,CO--NH--CH₃); 8.6 (s, 3H, CH); 9.05 (t, 3H, CO--NH--CH₂); 10.15 (d, 3H,C_(ar) --NH--CO)

¹³ C NMR DMSO-d₆ 66.6 MHz

26 (3CH₃); 43 (3CH₂); 88.8, 97.5, 99.2 (9C_(ar) --I); 129 (3C_(ar) --H);134.4 (3C_(ar) --CO); 143, 149, 150.5 (9C_(ar) --I); 165.6, 167.5, 169.7(12CO).

EXAMPLE 2

Preparation of the compound of formula: ##STR67##

3 g (0.014 mol) of trimesic acid, 29.16 g (0.044 mol) of 3-N-(hydroxyethyl)carbamoyl!-5-aminoacetamido-2,4,6-triiodobenzoic acidprepared according to the method described in U.S. Pat. No. 4,014,986,7.65 g (0.05 mol) of hydroxybenzotriazole, 10 ml of triethylamine and9.58 g (0.05 mol) of EDCI are dissolved in 0.8 l of DMF. After stirringof the mixture at room temperature for 12 h followed by evaporation ofthe solvent, the residue is triturated in CH₂ Cl₂. The solid obtained ispurified by dissolution in aqueous ammonia and is then precipitated inan acid medium.

28 g of the product in the form of a white powder are obtained,equivalent to a 90% yield.

TLC SiO₂ (AcOEt/isopropanol/NH₃, 35:35:40)

Rf: 0.15

¹ H NMR DMSO-d₆ 200 MHz

3.2 (m, 6H, CH₂ --CH₂ --OH); 3.5 (m, 6H, CH₂ --CH₂ OH); 4.2 (s, 6H,CONH--CH₂ --CONH); 8.6 (m, 3H, CONH--CH₂ CH₂ OH); 8.6 (s, 3H, CH); 9.06(t, 3H, CO--NH--CH₂ CO); 10.2 (d, 3H, C_(ar) --NH--CO).

¹³ C NMR 66.6 MHz DMSO-d₆

40.3 (3CH₂ CH₂ OH); 41.7 (3CONHCH₂ CONH); 59.2 (3CH₂ OH); 86.8, 97.5,99.3 (9C_(ar) --I); 129.5 (3C_(ar) --H); 134.4 (3C_(ar) --CO); 142.8,149, 150.2 (9C_(ar) iodinated); 165.6, 167.3, 167.5, 169.3, 169.7 (12CO).

EXAMPLE 3

Preparation of the compound of formula: ##STR68##

0.92 g (0.0048 mol) of EDCI is added to a solution of 0.31 g (0.001 mol)of 1,3,5,7-tetracarboxyadamantane prepared according to the methoddescribed in J. Org. Chem. (1992), 57, 358, 2.5 g (0.004 mol) of3-(N-methylcarbamoyl)-5-aminoacetamido-2,4,6-triiodobenzoic acid, 0.74 g(0.0048 mol) of hydroxybenzotriazole and 1.4 ml (0.01 mol) oftriethylamine in 50 ml of dimethylformamide. The mixture is stirred for12 hours at room temperature and then evaporated to dryness. The residueis taken up in 100 ml of CH₂ Cl₂ with stirring and is then filtered off.The solid obtained is dissolved in 20 ml of water in a sufficient amountof sodium hydrogen carbonate solution, and the solution isreprecipitated at pH 2. After filtration and drying, 2.5 g of a whitepowder are obtained, equivalent to a 92% yield.

TLC (SiO₂) Isopropanol/AcOEt/NH₃, 35:35:40

Rf: 0.15

¹ H NMR DMSO-d₆ 200 MHz

1.9 (s, 12H, adamantane CH₂); 2.7 (s, 12H, CH₃); 3.0 (m, 4H, CO₂ H); 3.9(s, 8H, CH₂); 7.5 (dq, 4H, CONH, CH₃); 8.5 (d, 4H, CO--NH--CH₂); 9.95(d, 4H, C_(ar) --NH--CO).

¹³ C NMR DMSO-d₆ 66.6 MHz

27 (CH₃); 38 (adamantane C); 42.5 (adamantane CH₂); 43 (CH₂); 88.5,97.5, 100.0 (C--I); 143, 149, 153 C_(ar)); 168, 170, 177 (CO).

EXAMPLE 4

Preparation of the compound of formula: ##STR69##

500 mg (0.001 mol) of 4,4',4",4'"-tetracarboxytetraphenylmethaneprepared according to the method described in Angew. Chem. Int. Ed.Engl., 25 (1986) no. 12, 1097-1098 and J.A.C.S. (1990) 112, 1546-1554,2.76 g (0.0044 mol) of3-(N-methylcarbamoyl)-5-aminoacetamido-2,4,6-triiodobenzoic acid, 0.674g (0.005 mol) of hydroxybenzotriazole and 0.7 ml (0.005 mol) oftriethylamine are dissolved in 100 ml of DMF. 0.843 g (0.005 mol) ofEDCI are introduced into the reaction mixture. After stirring for 24 hat room temperature, the solvent is removed under vacuum and the residueis crystallized in CH₂ Cl₂. The solid is solubilized in aqueous ammoniaand precipitated in an acid medium.

2.5 g of the product are obtained, equivalent to an 85% yield.

TLC (SiO₂) AcOEt/isopropanol/NH₄ OH, 35:35:40

Rf: 0.12

¹ H NMR DMSO-d₆ 200 MHz

2.7 (s, 12H, CH₃); 3.3 (m, 4H, CO₂ H); 4.1 (s, 8H, CH₂); 7.25, 7.9 (dd,16H, Φ--H); 8.4, 8.5 (dd, 4H, CO--NH--CH₃); 8.8 (m, 4H, CO--NH--CH₂);10.05 (d, 4H, Φ--NH--CO).

EXAMPLE 5

Preparation of the compound of formula: ##STR70##

2 g (0.0052 mol) of tetramethyl-1,3,5,7-tetracarboxy-2,6-dioxobicyclo1.3.3!nonane prepared according to the method described in J. Org. Chem.(1992) 57, 358 are stirred in 14 ml of 2N sodium hydroxide and 15 ml ofmethanol for 48 h at 50° C.

The solution is evaporated to dryness and the residue taken up in 10 mlof water. After the addition of 12N hydrochloric acid to pH 1, themixture is left to crystallize for 16 h. After filtration and drying,0.6 g of white powder are obtained, equivalent to a 35% yield.

TLC (SiO₂) MeOH/AcOEt, 5:5-Rf: 0.43

IR (KBr) 3000, 2960, 1680, 1440, 1400, 1280, 1240 cm⁻¹

¹³ C NMR DMSO-d₆ 66.6 MHz

28.1, 35.7 (CH₂); 42.4 (CH); 54.8 (C); 172.1 (CO); 208.5 (C═O)

By adopting the procedure described in Example 3 above, the compound ofthe title is obtained.

EXAMPLE 6

Preparation of the compound of formula: ##STR71##

1) Preparation of the compound of formula: ##STR72## N,N'-bis{N-2,4,6-triiodo-3-carboxy-5-(N-methylcarbamoyl)phenyl!carbamoylmethyl}-5-amino-2,4,6-triiodoisophthalamide

26.4 g (0.042 mol) of 2,4,6-triiodo-5-amino-N-methylisophthalamic acidare added rapidly to a solution of 10 g (0.0168 mol) of5-amino-2,4,6-triiodoisophthaloyl chloride in 30 cm³ ofdimethylacetamide with stirring. The mixture is then heated at 50° C.for 3 h and thereafter precipitated in HCl (10N). After stirring for 24h, the precipitate is filtered off, washed with water anddichloromethane and then dried.

20 g (67%) of product are obtained.

TLC (SiO₂) toluene/methyl ethyl ketone/HCOOH, 60:25:20

Rf: 0.13

¹³ C NMR DMSO-d₆ 66.6 MHz

170 ppm ##STR73## (amide group on aromatic ring) ##STR74## (carboxylgroup on aromatic ring) Aromatic C

151 ppm (NH₂); 150 ppm (NH--C═O); 149 ppm ##STR75## 147 ppm ##STR76##143 ppm (COOH)

Iodinated aromatic C

100 ppm; 98 ppm; 90 ppm; 82 ppm;

CH₂ (on amine) 43 ppm;

CH₃ ##STR77## 26 ppm.

2) Preparation of the compound of formula: ##STR78##

N,N'-bis{N-2,4,6-triiodo-3-carboxy-5-(N-methylcarbamoyl)phenyllcarbamoylmethyl}-5-N-(phthalimidoacetyl)amino!-2,4,6-triiodoisophthalamide

1.2 g (5.37×10⁻³ mol) of phthaloylglycyl chloride are added to asolution of 1 g (5.48×10⁻⁴ mol) of the product obtained in the precedingstep in 2 cm³ of dimethylacetamide with stirring. The reaction medium isstirred for 24 h at room temperature and is then precipitated in hotwater. The precipitate is filtered off, washed with hot water and thendichloromethane and dried.

TLC (SiO₂) ethyl acetate/isopropanol/NH₃, 35:35:40. Rf: 0.27

The product obtained is deprotected in a traditional manner by treatmentwith hydrazine. After coupling to trimesic acid according to the methoddescribed in Example 1 above, the product of the title is obtained.

EXAMPLE 7

Preparation of the compound of formula: ##STR79##

1) Preparation of the compound of formula: ##STR80##

300 g (0.38 mol) of 5-N-(phthalimidoacetyl)amino!-2,4,6-triiodoisophthaloyl chloride are addedto a solution of 258.9 g (1.149 mol) of1-deoxy-1-(2-hydroxyethylamino)-D-glucitol and tributylamine (273.9 ml;1.149 mol) in 2 liters of dimethylacetamide. The mixture is stirredovernight at room temperature. After evaporation of the solvent andprecipitation in dichloromethane, the product is dissolved in water andpurified by passing it through an ion exchange resin (Amberlite IRN 77).After evaporation, 350 g (80% Yld.) of product are obtained.

¹³ C NMR DMSO-d₆ 66.6 MHz

170, 167, 166, 165 ppm (C═O)

149, 143 ppm (aromatic C)

135, 132, 123 ppm (phthalimido aromatic C)

99, 91 ppm (iodinated aromatic C)

73, 71, 69 ppm (amine alcohol CH)

63, 59, 58.5, 57 ppm (amine alcohol CH₂)

52.5, 52, 49, 48.5 ppm (CH₂ α to N of the amine alcohol)

41 ppm (CH₂ α to the phthalimido).

2) Preparation of the compound of formula: HX₄

275 g (0.22 mol) of the compound of Example 7.1 are dissolved in 1.4liters of water in the presence of 33.2 ml (0.66 mol) of hydrazinehydrate. The mixture is heated to 80° C. for 2 hours and then, afterreturning to room temperature, acidified with 53 ml of hydrochloric acid(10N). The insoluble matter is filtered off and the solution is purifiedby passage through ion exchange resins (Amberlite IRA 67 and IRC 50).After evaporation, 188.7 g of product are obtained (Yld.=97%).

¹³ C NMR DMSO-d₆ 66.6 MHz

173, 171, 170 ppm (C═O)

149, 143 ppm (aromatic C)

99, 91 ppm (iodinated aromatic C)

73, 71, 69 ppm (amine alcohol CH)

63, 59, 58.5, 57 ppm (amine alcohol CH₂)

52.5, 52, 49, 48.5 ppm (CH₂ α to amine alcohol N)

45 ppm (CO--CH₂ --NH₂).

3) Preparation of the compound of the title

15 g (0.0146 mol) of the compound of Example 7.2 are dissolved in 320 mlof dimethylformamide in the presence of 0.927 g (4.4×10⁻³ mol) oftrimesic acid, 2,15 g (0.016 mol) of 1-hydroxybenzotriazole, 2.34 mol(0.0168 mol) of triethylamine and 3.05 g (0.0159 mol) of EDCI. Afterstirring for 24 hours at room temperature, the solvent is removed undervacuum and the residue is triturated in CH₂ Cl₂. After purification onsilanized silica (SiRP2, elution with water), 8.3 g of the expectedproduct are obtained (Yld.=58%).

¹³ C NMR DMSO-d₆ 66.6 MHz:

170, 167, 165.5 ppm (C═O)

149, 143 ppm (aromatic C)

134, 129.5 ppm (trimesic aromatic C)

99, 91 ppm (iodinated aromatic C)

10 73, 71, 69 ppm (amine alcohol CH)

63, 59, 58.5, 57 ppm (amine alcohol CH₂)

52.5, 52, 49, 48.5 ppm (CH₂ α to amine alcohol N)

43 ppm (CO--NH--CH₂ -CONH).

EXAMPLE 8

Preparation of the compound of formula: ##STR81## with X₄ as defined inExample 7

From the tetraacid obtained according to the method described in G. R.Newkome, C. N. Moorefield and G. R. Baker; Aldrichimica Acta, Vol. 25,No. 2, 1992, p. 31 and of the compound of Example 7.2, the compound ofthe title is prepared according to the coupling method described inExample 7.

EXAMPLE 9

Preparation of the compound of formula: ##STR82## with X₄ as defined inExample 7.

1) Preparation of the compound of formula: ##STR83##

150 g (0.146 mol) of the compound of Example 7.2 are added to a solutionof 400 ml of dimethylacetamide containing 35 ml of tributylamine and47.5 g (0.06 mol) of 5-N-(phthalimidoacetyl)amino!-2,4,6-triiodoisophthaloyl chloride. Thereaction medium is heated to 50° .C for 2 hours and then concentrated todryness. The product is then triturated in methylene chloride andthereafter purified by chromatography on silanized silica (SiRP2,elution with water). 110 g (Yld.=80%) of the expected product arethereby obtained.

¹³ C NMR DMSO-d₆ 66.6 MHz

170, 167, 166, 165 ppm (C═O)

149, 148.5, 143.5, 143 ppm (aromatic C)

135, 132, 123 ppm (phthalimido aromatic C)

99.5, 99, 91, 90.5 ppm (iodinated aromatic C)

73, 71, 69 ppm (amine alcohol CH)

63, 59, 58.5, 57 ppm (amine alcohol CH₂)

52.5, 52, 49, 48.5 ppm (CH₂ α to amine alcohol N)

44 ppm (CO--NH--CH₂ --CONH)

41 ppm (CH₂ α to phthalimido)

2) Preparation of the compound of formula: X₅ H

110 g (0.04 mol) of the compound of Example 9.1 are dissolved in 370 mlof water in the presence of 6 ml (0.12 mol) of hydrazine hydrate. Themixture is heated to 80° C. for 2 hours and then, after returning toroom temperature, acidified with 16 ml of hydrochloric acid (10N). Theinsoluble matter is filtered off and the solution is purified by passagethrough ion exchange resins (Amberlite IRA67 and IRL50). Afterevaporation, 99 g of product are obtained (Yld.-94%).

¹³ C NMR DMSO-d₆ 66.6 MHz

170, 168, 165 ppm (C═O)

149, 148.5, 143.5, 143 ppm (aromatic C)

99.5, 99, 91, 90.5 ppm (iodinated aromatic C)

73, 71, 69 ppm (amine alcohol CH)

63, 59, 58.5, 57 ppm (amine alcohol CH₂)

52.5, 52, 49, 48.5 ppm (CH₂ α to amine alcohol N)

45 ppm (NH--CO--CH₂ --NH₂)

43 ppm (CONH--CH₂ --CONH).

3) Preparation of the compound of the title

By reaction between the compound of Example 9.2 and trimesic acid underthe usual coupling conditions described in Example 7, the compound ofthe title is obtained in an 80% yield.

¹³ C NMR DMSO-d₆ 66.6 MHz

170, 167, 166, 165 ppm (C═O)

149, 148.5, 143.5, 143 ppm (aromatic C)

135, 127 ppm (trimesic aromatic C)

100, 99.5, 90.5, 90 ppm (iodinated aromatic C)

73, 71, 69 ppm (amine alcohol CH)

63, 59, 58.5, 57 ppm (amine alcohol CH₂)

52.5, 52, 49, 48.5 ppm (CH₂ α to amine alcohol N)

43 ppm (CONH--CH₂ --CONH).

EXAMPLE 10

Preparation of the compound of formula: ##STR84##

1) Preparation of the compound of formula: ##STR85##

150 g (0.19 mol) of 5- N-(phthalimidoacetyl)amino!-triiodoisophthaloylchloride are reacted with 78 g (0.578 mol) of N-methylaminobutanetriolaccording to the procedure described in Example 7.1. 186.2 g (Yld.=99%)of the diamidation product are thereby obtained, which product issubjected to hydrazinolysis under the conditions of Example 7.2 toobtain the expected product in a 74% yield.

¹³ C NMR DMSO-d₆ 66.6 MHz

171, 170, 165 ppm (C═O)

150, 144 ppm (aromatic C)

99, 90 ppm (iodinated aromatic C)

72, 66 ppm (amine alcohol CH)

63 ppm (amine alcohol CH₂)

55, 51 ppm (CH₂ α to amine alcohol N)

45 ppm (NH--CO--CH₂ --NH₂)

37, 34 ppm (CH₃ --N).

2) Preparation of the compound of formula: X₆ H

80 g (0.094 mol) of the compound of Example 10.1 are reacted with 30.7 g(0.039 mol) of 5-N-(phthalimidoacetyl)amino!-2,4,6-triiodoisophthalazoyl chlorideaccording to the procedure of Example 9.1. 72.4 g (Yld.=77%) of thediamidation product are thereby obtained, which product is subjected tohydrazinolysis under the conditions of Example 9.2 to obtain theexpected product in a 91% yield.

³ C NMR DMSO-d₆ 66.6 MHz

171, 170, 165 ppm (C═O)

150, 149.5, 144.5, 144 ppm (aromatic C)

100, 99.5, 90.5, 90 ppm (iodinated aromatic C)

72, 66 ppm (amine alcohol CH)

63 ppm (amine alcohol CH₂)

55, 51 ppm (CH₂ α to amine alcohol N)

45 ppm (NHCO--CH₂ --NH₂)

44 ppm (CONH--CH₂ --CONH)

37, 34 ppm (CH₃ --N).

3) Preparation of the compound of the title

By reaction between the compound of Example 10.2 and trimesic acid underthe usual coupling conditions described in Example 7, the compound ofthe title is obtained in a 90% yield.

¹³ C NMR DMSO-d₆ 66.6 MHz

170, 167, 166 165 ppm (C═O)

150, 149.5, 144.5, 144 ppm (aromatic C)

135, 127 ppm (trimesic aromatic C)

100, 99.5, 90.5, 90 ppm (iodinated aromatic C)

72, 66 ppm (amine alcohol CH)

63 ppm (amine alcohol CH₂)

55, 51 ppm (CH₂ α to amine alcohol N)

44 ppm (--CO--NH--CH₂ --CONH)

37, 34 ppm (CH₃ --N)

EXAMPLE 11 ##STR86##

1) Preparation of the compound of formula: X₇ H

208 g (0.24 mol) of 5-N-(phthalimidoacetyl)amino!-2,4,6-triiodoisophthaloyl chloride are addedto a solution of 416 g (1.2 mol) of bis(1-deoxy-D-sorbit-1-yl)-amine and100 ml (0.72 mol) of triethylamine in 2 liters of1-methyl-2-pyrrolidinone (NMP). The mixture is heated at 70° C. for 24hours. The insoluble matter is then filtered off and the solvent isremoved under vacuum. The product is then purified as in Example 7.1 andthereafter subjected to hydrazinolysis under the usual conditions(Example 7.2). It is then reacted with 0.42 equivalent of 5-N-(phthalimidoacetyl)amino!-2,4,6-triiodoisophthaloyl chloride under theconditions of Example 9.1 and thereafter subjected to hydrazinolysisunder the usual conditions (Example 9.2). The product is obtained in a51% overall yield.

¹³ C NMR DMSO-d₆ 66.6 MHz

170, 167, 166, 165 ppm (C═O)

149, 148.5, 143, 142.5 ppm (aromatic C)

99, 98.5, 91, 90.5 ppm (iodinated aromatic C)

73, 71, 69 ppm (amine alcohol CH)

63 ppm (amine alcohol CH₂)

54.5, 54, 49.5, 49 ppm (CH₂ α to amine alcohol N)

44 ppm (NHCO--CH₂ --NH₂)

43 ppm (CONH--CH₂ --CONH).

2) Preparation of the compound of the title

By reaction between the compound of Example 11.1 and trimesic acid underthe usual coupling conditions described in Example 7, the product of thetitle is obtained in an 80% yield.

¹³ C NMR DMSO-d₆ 66.6 MHz

170, 167, 166, 165 ppm (C═O)

149, 148.5, 143, 142.5 ppm (aromatic C)

135, 127 ppm (trimesic aromatic C)

99, 98.5, 91, 90.5 ppm (iodinated aromatic C)

73, 71, 69 ppm (amine alcohol CH)

63 ppm (amine alcohol CH₂)

54.5, 54, 49.5, 49 ppm (CH₂ α to amine alcohol N)

44 ppm (CONH--CH₂ --CONH).

EXAMPLE 12 ##STR87##

The product of Example 11.1 is reacted with 0.42 equivalent of 5-N-(phthalimidoacetyl)amino!-2,4,6-triiodoisophthaloyl chloride under theconditions of Example 9.1, and then subjected to hydrazinolysis in theusual manner (Example 9.2). Then, by coupling trimesic acid under theusual conditions described in Example 7, the product of the title isobtained.

EXAMPLE 13 ##STR88##

1) Preparation of the compound of formula: ##STR89##

119.5 g (0.13 mol) of5-(phthalimidoacetyl)amino!-2,4,6-triiodoisophthaloyl chloride are addedto a solution of 41.53 g (0.14 mol) of1-deoxy-1-(2-hydroxyethylamino)-D-glucitol and triethylamine (19.5 ml;0.14 mol) in 700 ml of diethylacetamide. The mixture is stirred at roomtemperature for 24 hours. 300 ml of water are added, and stirring ismaintained for 48 hours while heating at 45° C. The solvent is thenevaporated off under vacuum and the product is purified on ion exchangeresin (Amberlite IRN 77) and on silanized silica (SiRP2, elution withwater). 26 g (Yld.=38%) of product are obtained.

¹³ C NMR DMSO-d₆ 66.6 MHz

170, 169.5, 167, 165 ppm (C═O)

150, 147, 142 ppm (aromatic C)

135, 132, 124 ppm (phthalimido C)

100, 98, 90 ppm (iodinated aromatic C)

73, 71, 69 ppm (amine alcohol CH)

63, 59, 58 ppm (amine al cohol CH₂)

52.5, 52, 49, 48.5 ppm (CH₂ α to amine alcohol N)

41 ppm (CH₂ α to phthalimido).

2) Preparation of the compound of formula: X₉ H

25 g (0.026 mol) of the product of Example 13.1 are subjected tohydrazinolysis under the usual conditions described in Example 7.2 toobtain the expected product in a 55% yield.

¹³ C NMR DMSO-d₆ 66.6 MHz

172, 171, 170 ppm (C═O)

157, 147, 142 ppm (aromatic C)

100, 98, 90 ppm (iodinated aromatic C)

73, 71, 69 ppm (amine alcohol CH)

63, 59, 58 ppm (amine alcohol CH₂)

52.5, 52, 49, 48.5 ppm (CH₂ α to amine alcohol N)

43 ppm (NHCO--CH₂ --NH₂).

3) Preparation of the compound of the title

11.5 g (0.014 mol) of the product of Example 13.2 are reacted withtrimesic acid under the usual coupling conditions described in Example 7to obtain the product of the title in a 51% yield.

¹³ C NMR DMSO-d₆ 66.6 MHz

170, 167, 165 ppm (C═O)

157, 147, 142 ppm (aromatic C)

134, 130 ppm (trimesic aromatic C)

100, 98, 90 ppm (iodinated aromatic C)

73, 71, 69 ppm (amine alcohol CH)

63, 59, 58 ppm (amine-alcohol CH₂)

52.5, 52, 49, 48.5 ppm (CH₂ α to amine alcohol N)

42 ppm (CONH--CH₂ --CONH).

EXAMPLE 14

Preparation of the compound of the formula

The product of Example 13.2 is reacted with 0.42 equivalent of 5-N-(phthalimidoacetyl)amino!-2,4,6-triiodoisophthaloyl chloride under theconditions of Example 9.1 and then subjected to hydrazinolysis in theusual manner (Example 9.2). Then, by coupling with trimesic acid underthe conditions of Example 7, the product of the title is obtained in a12% overall yield.

¹³ C NMR DMSO-d₆ 66.6 MHz

170, 167, 166, 165 ppm (C═O)

150, 149.5, 147, 146.5, 142, 142.5 ppm (aromatic C)

135, 128 ppm (trimesic aromatic C)

100, 99.5, 98, 97.5, 90.5, 90 ppm (iodinated aromatic C)

73, 71, 69 ppm (amine alcohol CH)

63, 59, 58 ppm (amine alcohol CH₂)

52.5, 52, 49, 48.5 ppm (CH₂ α to amine alcohol N)

44 ppm (CONH--CH₂ --CONH).

EXAMPLE 15

Preparation of the compound: ##STR90##

5-Amino-2,4,6-triiodoisophthalic acid is N-monomethylated (Yld.=62%)according to a procedure described in FR Patent no. 2,110,179. Thisproduct is then chlorinated, acylated with chloroacetyl chloride(Yld.=70%), diamidated in the presence of1-deoxy-1-(2-hydroxyethylamino)-D-glucitol (Yld.=65%) and reacted withmethylamine (Yld.=50%) under the conditions described in Patent WO93/1007 of 27th May 1993. The product thereby obtained may be coupledwith trimesic acid under the usual conditions (Example 7) to obtain theproduct of the title.

We claim:
 1. Polyiodinated compounds with a single molecular weighthaving a molecular concentration of iodine of greater than 20% byweight, a molecular weight above 2,000 and below 50,000, and containingat least one group of formula ##STR91## with w=Σ₀ ^(n) 2^(n) andw'=2^(n) , n representing an integer from 0 to 4, the groups Q, whichmay be identical to or different from one another, represent a singlebond or a group selected from the group consisting of: ##STR92## inwhich: R₁ is selected from the group consisting of an alkylene grouphaving a linear or branched C₁ -C₁₀ chain, a hydroxy- orpolyhydroxyalkylene group having a linear or branched C₁ -C₁₀ chain, a(C₁ -C₅ alkoxy)alkylene group having a linear or branched C₁ -C₁₀ chain,a hydroxy- or polyhydroxy(C₁ -C₁₀ alkoxy)alkylene group having a linearor branched chain, and a single bond, and the R₂ groups identical ordifferent being selected from H, the group consisting of an alkyl grouphaving a linear or branched C₁ -C₁₀ chain, a hydroxy- orpolyhydroxyalkyl group having a linear or branched C₁ -C₁₀ chain, a (C₁-C₅ alkoxy)alkyl group having a linear or branched C₁ -C₁₀ chain and ahydroxy- or polyhydroxy(C₁ -C₅ alkoxy)alkyl group having a linear orbranched chain;the groups B₁, which may be identical to or differentfrom one another, represent the residue of an aromatic group containingat least three iodine atoms, of formula: ##STR93## in which R₃ isselected from the group consisting of:a group --COO⁻ M⁺ with M⁺representing H⁺ or a physiologically acceptable cation of an organic orinorganic base, ##STR94## and a group ##STR95## in which R₅ and R₆,which may be identical to or different from one another, represent H ora linear or branched C₁ -C₁₀ alkyl, linear or branched C₁ -C₁₀ hydroxy-or polyhydroxyalkyl, linear or branched C₁ -C₁₀ (C₁ -C₅ alkoxy)alkyl orlinear or branched C₁ -C₁₀ hydroxy- or polyhydroxy(C₁ -C₅ alkoxy)alkylgroup, or R₅ and R₆ together form a C₄ -C₈ alkylene, C₄ -C₈hydroxyalkylene, or C₄ -C₈ polyhydroxyalkylene group having a linear orbranched chain which is optionally interrupted by one or more atomsselected from S, O, P and N, so that R₅ and R₆, with the nitrogen atomto which they are linked, form a 5- to 12-membered nitrogenousheterocycle optionally substituted with one or more hydroxyl groups orC₁ -C₄ hydroxy- or polyhydroxyalkyl groups having a linear or branchedchain and optionally containing one or more additional hetero atomsselected from S, O, P and N, R₄ represents a group selected from thegroup consisting of R₃ and a group of formula Q--B₄, Q being as definedabove and B₄ representing a group: ##STR96## in which R₇ and R₈, whichmay be identical to or different from one another, represent R₃, thegroups B₃, which may be identical to or different from one another, areselected from the group consisting of: ##STR97## in which R₅ has themeanings given above.
 2. Polyiodinated compounds of formula I:

    A--(X).sub.m                                               (I)

with a molecular weight above 2,000 and below 50,000 in which: Arepresents the residue of a polyfunctional molecule containing either acentral tri- or tetrasubstituted carbon atom, a central trisubstitutedphosphorus or nitrogen atom or a trisubstituted ##STR98## group and/orat least one aromatic or non-aromatic carbocycle optionally containingone or more iodine atoms, or at least one aromatic or non-aromaticheterocycle containing from 1 to 4 hetero atoms selected from the groupconsisting of O, S, N and P, to which residue are bound m groups X via mgroups selected from the group consisting of --CO--, ##STR99## thegroups X, which may be identical to or different from one another,represent the groups: ##STR100## with w, w', Q, B₁ and B₃ as defined inclaim 1, and m represents an integer from 2 to
 12. 3. Polyiodinatedcompounds of formula I:

    A--(X).sub.m                                               (I)

with a molecular weight above 2,000 and below 50,000, in which: Arepresents: (a) a residue of a polyfunctional molecule containing acentral carbon atom, selected from the group consisting of residues offormula CR₉ (R₁₀ --Y.paren close-st.₃ in which R₉ represents a hydrogenatom, a C₁ -C₆ alkyl or C₅ -C₁₀ aryl group or a group (R₁₀ --Y), R₁₀being selected from the group consisting of C₁ -C₆ alkylene, C₅ -C₁₀arylene, (C₁ -C₁₀ alkyl) (C₅ -C₁₀ arylene) and (C₅ -C₁₀ aryl) (C₁ -C₆alkylene) group, alkylene groups being optionally interrupted by one ormore oxygen atoms, and alkyl, alkylene, aryl and arylene groups beingoptionally substituted with one or more OH groups, Y being selected fromthe group consisting of an --O--, --CO-- group and a group ##STR101## R₅being as defined in claim 1, (b) optionally polycyclic (C₅-C₁₂)cycloalkyl residues optionally containing from 1 to 6 iodine atomsand from 2 to 12 identical or different substituents of formula --R₁₁--(--Y.paren close-st._(q) , q representing an integer from 1 to 3, R₁₁being a single bond or a linear or branched C₁ -C₆ alkylene groupoptionally substituted with one or more OH groups and/or interrupted byone or more oxygen atoms, and Y being as defined above, (c) monocyclicor bicyclic C₅ -C₁₂ aromatic hydrocarbon residues optionally containingfrom 3 to 6 iodine atoms and optionally containing one or moresubstituents selected from the group consisting of OH, NH₂, C₁ -C₆alkyl, C₁ -C₆ (hydroxy- or polyhydroxy)alkyl, COOH, COOR₁₁, --CO--NHR₁₂and --NR₆ COR₅, R₁₂ representing C₁ -C₄ alkyl group and containing from2 to 12 substituents of formula --R₁₁ --(--Y)--_(q) , q and R₁₁ being asdefined above and Y representing a group selected from the groupconsisting of --O--, --CO--, ##STR102## (d) optionally aromaticmonocyclic or bicyclic, heterocyclic residue containing from 5 to 10ring-members comprising 1 to 4 hetero atoms selected from the groupconsisting of O, S, N and P, optionally substituted with 3 to 6identical or different substituents selected from the group consistingof ═O, and containing from 3 to 12 substituents of the formula --R₁₁--(--Y)_(q) , (e) optionally cyclic residues containing from 2 to 18aromatic or heterocyclic ring-systems as defined above, linked to oneanother through groups --R₁₁ --, --OR₁₁ --, R₁₁ being as defined above,this residue containing from 3 to 12 substituents of formula --R₁₁--(--Y.paren close-st._(q) , R₁₁, Y and q being as defined above, thegroups X, which may be identical or different, represent the groups:##STR103## and w=Σ₀ ^(n) 2^(n) and w'=2^(n), n representing an integerfrom 0 to 4, m represents an integer from 2 to 12, B₃ being defined asin claim 1, the groups Q, which may be identical to or different fromone another, represent a single bond or a group selected from the groupconsisting of: ##STR104## in which: R₁ is selected from the groupconsisting of a single bond, an alkylene group having a linear orbranched C₁ -C₁₀ chain, a hydroxy- or polyhydroxyalkylene group having alinear or branched C₁ -C₁₀ chain, a (C₁ -C₅ alkoxy)alkylene group havinga linear or branched C₁ -C₁₀ chain and a hydroxy- or polyhydroxy-(C₁ -C₅alkoxy)alkylene group having a linear or branched chain, the alkylenechain being optionally interrupted by one or more oxygen atoms, and R₂is selected from H, the group consisting of an alkyl group having alinear or branched C₁ -C₁₀ chain, a hydroxy- or polyhydroxyalkyl grouphaving a linear or branched C₁ -C₁₀ chain, a (C₁ -C₅ alkoxy)alkyl grouphaving a linear or branched C₁ -C₁₀ chain and a hydroxy- orpolyhydroxy(C₁ -C₅ alkoxy)alkyl group having a linear or branched chain;the groups B₁, which may be identical to or different from one another,represent the residue of an aromatic group containing at least threeiodine atoms of formula: ##STR105## in which R₃ is selected from thegroup consisting of--COO⁻ M⁺ with M⁺ representing H⁺ or aphysiologically acceptable cation of an organic or inorganic base, agroup ##STR106## and a group ##STR107## in which R₅ and R₆, which may beidentical to or different from one another, represent H or a liner orbranched C₁ -C₁₀ alkyl, linear or branched C₁ -C₁₀ (hydroxy- orpolyhydroxy)alkyl, linear or branched C₁ -C₁₀ (C₁ -C₅ alkoxy)alkyl orlinear or branched C₁ -C₁₀ hydroxy- or polyhydroxy(C₁ -C₅ alkoxy)alkylgroup, or R₅ and R₆ together form a C₄ -C₈ alkylene, C₄ -C₈hydroxyalkylene or C₄ -C₈ polyhydroxyalkylene group having a linear orbranched chain which is optionally interrupted by one or more atomsselected from the group consisting of S, O, P and N, so that R₅ and R₆,with the nitrogen atom to which they are linked, form a 5- to12-membered nitrogenous heterocycle optionally substituted with one ormore hydroxyl groups or C₁ -C₄ (hydroxy- or polyhydroxy)alkyl groupshaving a linear or branched chain and optionally containing one or moreadditional hetero atoms selected from S, O, P and N, R₄ represents agroup selected from the group consisting of R₃ and the groups of formulaQ--B₄, Q being as defined above and B₄ representing a group ##STR108##in which R₇ and R₈, which may be identical to or different from oneanother, represent R₃ as defined above.
 4. Polyiodinated compoundsaccording to claim 3, characterized in that A is selected from the groupconsisting of(a) residues of formula C(R₁₀ --Y.paren close-st.₄ ,R₁₀representing a methylene, phenylene or phenylmethylene group or a --CH₂--O--CH₂ -- or --CH₂ --O--(CH₂)₂ -- group, and Y being as defined inclaim 3; (b) cycloalkyl residues selected from cyclohexyl and adamantylsubstituted with 3 or 4 substituents q R₁₁ --(--Y.paren close-st._(q) asdefined in claim 3; (c) phenyl groups optionally substituted with 3 or 4iodine atoms or biphenyl groups optionally substituted with 4 to 6iodine atoms and optionally containing from 3 to 6 substituents offormula R₁₁ --(--Y.paren close-st._(q) , q, R₁₁ and Y being as definedin claim 3; (d) heterocyclic residues consisting of a2,4,6-trioxo-1,3,5-triazine group substituted on the nitrogen atoms with3 substituents of formula --R₁₁ --(--Y.paren close-st._(q) as defined inclaim 3; (e) macrocyclic residues consisting of 6 to 8 phenyl residueseach substituted with one or more substituents selected from the groupconsisting of OH, NH₂, C₁ -C₆ alkyl, C₁ -C₆ hydroxy- orpolyhydroxyalkyl, COOH, COOR₁₁, --CO--NHR₁₂ and --NR₆ COR₅, R₁₁representing a C₁ -C₄ alkyl group, and one or more groups of the formulaR₁₁ --(--Y.paren close-st._(q) as defined above with q=1, the phenylresidues being linked to one another through a methylene group, or acyclodextrin composed of 6 to 8 glucosyl residues linked to one anotherthrough a glycosidic linkage, one or more OH groups of said glucosylresidues being optionally substituted with a carboxymethyl residue, oneor more OH groups of said glucosyl residues being replaced by an --O--group, or macrocylic residue containing more than one nitrogen or aderivative of a polyaminocarboxylic acid residue.
 5. Polyiodinatedcompounds according to claim 3, in which the groups B₁ are selected fromthe group consisting of: ##STR109##
 6. Polyiodinated compounds accordingto claim 3, in which the group Q is selected from the group consistingof: ##STR110## r being an integer from 1 to
 5. 7. Polyiodinatedcompounds according to claim 3, in which R₃ is selected from the groupconsisting of: ##STR111##
 8. Polyiodinated compounds according to claim3, characterized in that they have the formula V: ##STR112## w=Σ₀ ^(n)2^(n) and w'=2^(n) (n representing an integer from 0 to 4) in which A isdefined as in claim 3,Q represents a group ##STR113## and B₃ representsa group: ##STR114## and B₁ represents a group ##STR115## in which R₃ andR₄ are selected from the group consisting of CO⁻ ₂ M⁺ ##STR116## 9.Polyiodinated compounds characterized in that they are selected from thegroup consisting of: ##STR117## with: ##STR118##
 10. Contrast medium,characterized in that it contains at least one compound according toclaim
 3. 11. Contrast medium according to claim 10, characterized inthat it comprises an aqueous solution of the compound or compounds. 12.Polyiodinated compounds of generic formula I:

    A--(X).sub.m                                               (I)

in which: A represents the residue of a polyfunctional moleculecontaining either a central tri- or tetrasubstituted carbon atom, acentral trisubstituted phosphorus or nitrogen atom or a trisubstituted##STR119## group and/or at least one aromatic or non-aromatic carbocycleoptionally containing one or more iodine atoms, or at least one aromaticor non-aromatic heterocycle containing from 1 to 4 hetero atoms selectedfrom O, S, N and P, to which residues are bound m groups X viafunctional groups selected from the group consisting of --CO--,##STR120## --O--, and >NCOR₅ ; the groups X, which may be identical toor different from one another are selected from the group consisting ofthe group consisting of:

    --Q--B.sub.1                                               (A),

    --Q--A.sub.1 --(Q--B.sub.1).sub.m'                         (B),

m' representing from 2 to 11; and

    --Q--B.sub.2 --Q--B.sub.1                                  (C)

m represents an integer from 3 to 12, the groups Q, which may beidentical or different from one another, represent a single bond or agroup selected from: ##STR121## in which: R₁ is selected from the groupconsisting of an alkylene group having a linear or branched C₁ -C₁₀chain, a hydroxy- or polyhydroxyalkylene group having a linear orbranched C₁ -C₁₀ chain, a (C₁ -C₅ alkoxy)alkylene group having a linearor branched C₁ -C₁₀ chain, a hydroxy- or polyhydroxy(C₁ -C₅alkoxy)alkylene group having a linear or branched chain, and a singlebond, and the R₂ groups identical or different being selected from thegroup consisting of H, an alkyl group having a linear or branched C₁-C₁₀ chain, a hydroxy- or polyhydroxyalkyl group having a linear orbranched C₁ -C₁₀ chain, a (C₁ -C₅ alkoxy)alkyl group having a linear orbranched C₁ -C₁₀ chain and a hydroxy- or polyhydroxy(C₁ -C₅ alkoxy)alkylgroup having a linear or branched chain; the groups B₁, which may beidentical to or different from one another, represent the residue of anaromatic group containing at least three iodine atoms, of formula:##STR122## in which R₃ is selected from the group consisting of:a group--COO⁻ M⁺ with M⁺ representing H⁺ or a physiologically acceptable cationof an organic or inorganic base, a group ##STR123## and group ##STR124##in which R₅ and R₆, which may be identical to or different from oneanother, represent H or a linear or branched C₁ -C₁₀ alkyl, linear orbranched C₁ -C₁₀ hydroxy- or polyhydroxyalkyl, linear or branched C₁-C₁₀ (C₁ -C₅ alkoxy)alkyl or linear or branched C₁ -C₁₀ hydroxy- orpolyhydroxy(C₁ -C₅ alkoxy)alkyl group, or R₅ and R₆ together form a C₄-C₈ alkylene, C₄ -C₈ hydroxyalkylene or C₄ -C₈ polyhydroxyalkylene grouphaving a linear or branched chain which is optionally interrupted by oneor more atoms selected from the group consisting of S, O, P and N, sothat R₅ and R₆, with the nitrogen atom to which they are linked, form a5- to 12-membered nitrogenous heterocycle optionally substituted withone or more hydroxyl groups or C₁ -C₄ hydroxy- or polyhydroxyalkylgroups having a linear or branched chain and optionally containing oneor more additional hetero atoms selected from the group consisting of S,O, P and N, R₄ represents a group selected from the group consisting ofR₃ and a group of formula Q--B₄, Q being as defined above and B₄representing a group: ##STR125## in which R₇ and R₈, which may beidentical to or different from one another, represent R₃, A₁ is selectedfrom the group consisting of groups A, with the proviso that at leastone group --CO--, ##STR126## or >NCOR₅ is replaced by a single bond, B₂is selected from the group consisting: ##STR127## in which R₄ and R₅have the meanings given above, with the proviso that said compoundscontain a zero overall electrical charge or at least two anionic chargeswhen A.paren open-st.X)_(m) =A(QB₁)₃, and that said compounds have amolecular weight above 2,000 and below 50,000 and a molecularconcentration of iodine greater than 20%.
 13. Polyiodinated compoundsaccording to claim 1, in which the groups B₁ are selected from the groupconsisting of: ##STR128##
 14. Polyiodinated compounds according to claim1, in which the group Q is selected from the group consisting of:##STR129## r being an integer from 1 to
 5. 15. Polyiodinated compoundsaccording to claim 1, in which R₃ is selected from the group consistingof: ##STR130##
 16. Contrast medium, characterized in that it contains atleast one compound according to claim
 1. 17. Contrast medium,characterized in that it contains at least one compound according toclaim
 1. 18. Polyiodinated compounds of formula I:

    A.paren open-st.X).sub.m                                   (I)

with a molecular weight above 2,000 and below 50,000, in which: Arepresents: (a) a residue of a polyfunctional molecule containing acentral carbon atom, selected from the group consisting of residues offormula CR₉ (R₁₀ --Y.paren close-st.₃ in which R₉ represents a hydrogenatom, a C₁ -C₆ alkyl or C₅ -C₁₀ aryl group or a group (R₁₀ --Y), R₁₀being selected from the group consisting of C₁ -C₆ alkylene, C₅ -C₁₀arylene, (C₁ -C₁₀ alkyl) (C₅ -C₁₀ arylene) and (C₅ -C₁₀ aryl) (C₁ -C₆alkylene) group, alkylene groups being optionally interrupted by one ormore oxygen atoms, and alkyl, alkylene, aryl and arylene groups beingoptionally substituted with one or more OH groups, Y being selected fromthe group consisting of an --O--, --CO-- group and a group ##STR131## R₅being as defined in claim 1, (b) optionally polycyclic (C₅-C₁₂)cycloalkyl residues optionally containing from 1 to 6 iodine atomsand from 2 to 12 identical or different substituents of formula --R₁₁--(--Y.paren close-st._(q) , a representing an integer from 1 to 3, R₁₁being a single bond or a linear or branched C₁ -C₆ alkylene groupoptionally substituted with one or more OH groups and/or interrupted byone or more oxygen atoms, and Y being as defined above, (c) monocyclicor bicyclic C₅ -C₁₂ aromatic hydrocarbon residues optionally containingfrom 3 to 6 iodine atoms and optionally containing one or moresubstituents selected from the group consisting of OH, NH₂, C₁ -C₆alkyl, C₁ -C₆ (hydroxy- or polyhydroxy)alkyl, COOH, COOR₁₁, --CO--NHR₁₂and --NR₆ COR₅, R₁₂ representing C₁ -C₄ alkyl group and containing from2 to 12 substituents of formula --R₁₁ --(--Y.paren close-st._(q) , q andR₁₁ being as defined above and Y representing a group selected from thegroup consisting of --O--, --CO--, ##STR132## (d) optionally aromaticmonocyclic or bicyclic, heterocyclic residue containing from 5 to 10ring-members comprising 1 to 4 hetero atoms selected from the groupconsisting of O, S, N and P, optionally substituted with 3 to 6identical or different substituents selected from the group consistingof ═O, and containing from 3 to 12 substituents of formula the --R₁₁--(--Y.paren close-st._(q) , q being defined above, (e) optionallycyclic residues containing from 2 to 18 aromatic or heterocyclicring-systems as defined above, linked to one another through groups--R₁₁₋₋, --OR₁₁ --, R₁₁ being as defined above, this residue containingfrom 3 to 12 substituents of formula --R₁₁ --(--Y.paren close-st._(q) ,R₁₁, Y and q being as defined above, the groups X, which may beidentical or different, represent the groups: ##STR133## and w=Σ₀ ^(n)2^(n) and W'=2^(n), n representing an integer from 0 to 4, m representsan integer from 2 to 12, B₃ being defined as in claim 1, the groups Q,which may be identical to or different from one another, represent asingle bond or a group selected from the group consisting of: ##STR134##in which: R₁ is selected from the group consisting of a single bond, analkylene group having a linear or branched C₁ -C₁₀ chain, a hydroxy- orpolyhydroxyalkylene group having a linear or branched C₁ -C₁₀ chain, a(C₁ -C₅ alkoxy)alkylene group having a linear or branched C₁ -C₁₀ chainand a hydroxy- or polyhydroxy-(C₁ -C₅ alkoxy)alkylene group having alinear or branched chain, the alkylene chain being optionallyinterrupted by 1 to 4 oxygen atoms, and R₂ is selected from H, the groupconsisting of an alkyl group having a linear or branched C₁ -C₁₀ chain,a hydroxy- or polyhydroxyalkyl group having a linear or branched C₁ -C₁₀chain, a (C₁ -C₅ alkoxy)alkyl group having a linear or branched C₁ -C₁₀chain and a hydroxy- or polyhydroxy(C₁ -C₅ alkoxy)alkyl group having alinear or branched chain; the groups B₁, which may be identical to ordifferent from one another, represent the residue of an aromatic groupcontaining at least three iodine atoms of formula: ##STR135## in whichR₃ is selected from the group consisting of --COO⁻ M⁺ with M⁺representing H⁺ or a physiologically acceptable cation of an organic orinorganic base,a group ##STR136## and a group ##STR137## in which R₅ andR₆, which may be identical to or different from one another, represent Hor a liner or branched C₁ -C₁₀ alkyl, linear or branched C₁ -C₁₀(hydroxy- or polyhydroxy)alkyl, linear or branched C₁ -C₁₀ (C₁ -C₅alkoxy)alkyl or linear or branched C₁ -C₁₀ hydroxy- or polyhydroxy(C₁-C₅ alkoxy)alkyl group, or R₅ and R₆ together form a C₄ -C₈ alkylene, C₄-C₈ hydroxyalkylene or C₄ -C₈ polyhydroxyalkylene group having a linearor branched chain which is optionally interrupted by one or more atomsselected from the group consisting of S, O, P and N, so that R₅ and R₆,with the nitrogen atom to which they are linked, form a 5- to12-membered nitrogenous heterocycle optionally substituted with one ormore hydroxyl groups or C₁ -C₄ (hydroxy- or polyhydroxy)alkyl groupshaving a linear or branched chain and optionally containing one or moreadditional hetero atoms selected from S, O, P and N, R₄ represents agroup selected from the group consisting of R₃ and the groups of formulaQ--B₄, Q being as defined above and B₄ representing a group ##STR138##in which R₇ and R₈, which may be identical to or different from oneanother, represent R₃ as defined above.